Dr. Ellisen is seeking training in the field of telomere biology following a successful series of collaborations resulting in the cloning and initial characterization of the gene for the human telomerase protein catalytic subunit. His project as described below ties in well with the work of his mentor, Dr. Daniel Haber, a successful and dedicated scientist at the Massachusetts General Hospital/Harvard Medical School well known in the field of cancer biology. The research environment and the collaborations Dr. Ellisen has established will provide excellent opportunities for his training leading to research independence. The ends of linear eukaryotic chromosomes are composed of specialized DNA-protein structures called telomeres, whose integrity is essential for normal cell growth. Telomeres are maintained by the enzyme telomerase, an RNA-dependent DNA polymerase which adds sequences to the 3' telomeric end of the chromosome. Telomerase enzymatic activity is required for long-term proliferation of stem cells; its overexpression in vitro overcomes cellular senescence, and its upregulation in vivo is associated with progression to malignancy. The overall goal of this research project is to demonstrate whether changes in telomerase enzymatic activity significantly affect normal cell differentiation and malignant cell growth. Three hypotheses will be tested. First, that increasing telomerase enzymatic activity in primary blood stem cells will expand their capacity for self-renewal, but may in turn block differentiation and be leukemogenic. Second, that blocking telomerase activity in tumor cells will cause growth arrest and death via an uncharacterized telomere-sensing pathway. Third, that novel human proteins which interact physically with telomerase and which have important telomere-regulatory activity can be isolated. This work should further our understanding of the how events at the telomere regulate normal and malignant cell growth.